1-formyl-1-(3-keto-6-carboalkoxy-hexyl)-2-keto-10-methyl-1, 2, 5, 8, 9, 10-hexahydronaphthalene



United Stares 1 FORIVIYL 1 (3 KE'IQ 6 CARBOALKOXY- HEXYL) 2 KETO 1'3 METHYL 1,2,5,8,9,10- HEXAHYDRONAPHTHALENE Martin W. Farrar, Webster Groves, M0., assignor to Monsanto Chemical Company, St. Louis, Mo., 2 corporation of Delaware No Drawing. Application June 14, 1954 Serial No. 436,721

2 Claims. (Cl. 260468) 0 O h 15 R0 CHzCHaCHz CH=CHg atent O particularly a member of the cyelopentanodirnethylpolyhydrophenanthrene series, namely a 17-formyl-cyc1opentano-10,13 dimethy1-A -decahydrophenanthren- The sequence of steps or series of reactions proceeding to the 17-forrny1-cyc1opentanoA -decahydrophenanthren-3-one for purposes of this invention is outlined schematically in the following diagram.

lg R0 H OH He=0 /RI OH -o 7 7 HO\ RO\J RO\ R0\ IV v ' hydronaphthalene, B. P. 122-123 The initial reactant of the-process outlined in the foregoing diagram, namely l-(hydroxy) methyleh'e-Z-ketd- 10-methyl-1,2,5,8,9,l0-hexahydronaphthalene Egon as will be obvious to those skilled in the art contains two asymmetric carbon atoms. As a result thereof such exists in the=form of four optically'active isomers or two racemates, i. e. cis-and trans racemic mixtures of the dextro and levo optically active isomers. All such forms per se or in any combination thereof may be employed in the process outlined herein. The initial reactant (compound I) is prepared by the formylation of the corresponding 2-keto 10 methyl-l,2,5,8,9,IO-hexahydronaphthalene I employing ethyl formate in the presence of sodium'methylate. As illustrative of such is the following Example A To a suitable reaction vessel is charged 17.3 parts by Weight (substantially 0.32 mol) of solid sodium methylate, 75 parts by weight of anhydrous benzene and 37 parts by weight (substantially 0.5 mol) of ethyl formate while maintaining the temperature at about-2O-25 C. The suspension so obtained is then agitated for about 20-30minutes employing a nitrogen atmosphere and hexahydronaphthalene is obtained from dl-cis-2- keto-lmethyl-l,2,5,8,9,IO-hexahydronaphthalene.

In the first step of the process of the foregoing diagram l (hydroxy) methylene 2 keto l0 methyl 1,2,5,-

8,9,IO-hexahydronaphthalene-is reacted with a 5-keto-6- heptanoic acid ester of the'formula u n 1 a nooomomcmocn=om where R is a short chain alkyl radical such as methyl, ethyl, propyl, butyl, etc., in an anhydrousmedia in the presence of a quaternary ammonium alkoxide and an inert solvent such as dioxane, isopropanohbutanol, isobutanol, tert. butanol, pentasol, etcu In general temperatures in the range of 0 to C. can be employed, however, it is preferred that thereaction temperature be about 10 to 30 C. As illustrative of the preparation of the l-heptanoic acid ester adduct (compound II) is the following.

; Example I i To a suitable reaction vessel is addedand intimately mixed 14.1 parts by weight of the levo-rotatory isomer 'of trans-l-(hydroxy) methylene-2-keto-l0-methyl-1,2,5,8,

9,10-hexahydronaphthalene, 14.9 parts by weight of 5- keto-fi-heptenoic .acid methyl ester, and 15.6 parts by weight of tert. butanol and them'ix cooled to 10-15 C.

v Thereupon approximately 2.4 parts by Weight of a 29.8%

' over a period of about 15 minutes.

then cooled to about 10 C. Thereupon approximately I 16.1 parts by Weight (substantially 0.1 mol) of the levo- V rotatory form of trans-Z-ketoQlQ-methyl-1,2,5,8,9,10-hexahydronaphthalene I dissolved in 150 parts by weight of benzene is added and themixture agitated for about 3 hours at about 15 C. The reaction mass so obtained is then quenched with cold dilute sulfuric acid (20 parts by weight sulfuric acid in 125 parts by weight of Water) while maintaining the temperature at about 15 C. and

agitating for about 5 minutes. "The aqueous layer is separated and extracted withseveral small portions of 7 f7 benzene; The benzene extracts are combined with the original organic layer and the combined mix subjected to vacuum distillation. The light tan oily residue so obtained consistsessentially by weight) of the 1'- (hydroxy) methylene derivative of the levo-rotatory form of trans 2 -keto-lO-rnethyl-l,2,5,8,9,10-hexahydronaphthalene. I'The oil is admixed with parts by Weight of rnethanol and with agitation heated to about '50 C.

While constantly agitating 400part's by weight of an aqueous 5% copper acetate solution 'is slowly; added. The precipitate, namely the copper ehelate of the 1- (hydroxy) methylene derivative of the levo-rotatory form of trans 2 -'keto 10 methyl l,2 ,5,8,9,l0 --hexahydro-' naphthalene, is filtered off, washed with methanol, and

then 'slurried with 87; parts; by weight of benzene: To

of the formula by weight n-butanol solution of benzyltrimethylammonium n-buto'xide admixed with approximately 4 parts by weight of tert. butanol is added to the agitated mixture The mix is then held at 2025 C. for about 16 hours, seeded with a minute amount of the final product and then held at 20-25 C. for about 48 hours. To the resultant mass is added with agitation approximately 25 parts by weight of petroleum ether and the mix cooled to about 0 C. The precipitate.

is filtered oif, washed with pertoleum ether, then with Water and dried. The hite crystalline product so, ob-

tained is the levo-rotatory'isomer of trans-1-formyl-1-(3- I keto 6-carbomethoxy-hexyl)-2-keto-10-methy1 1,258.9. l0-hexahydronaphthalene M. P. 66-67 C. [a] =-2O6 (C=2,CHC13). In like manner dl-trans-l-formyl l-(3-keto-6-carbomethoxy-hexyl) 2 keto-lO-methyl-1,2,5,8,9,10-hexahydronaphthalene is obtained from dl-trans-l-(hydroxy) methylene 2 keto-l0-methyl-1,2,5,8,9,IO-hexahydronaphthalene. r

In the process described in Example I other quaternary ammonium alkoxides may be employed although benzyltrimethyl ammonium n-butoxide is preferred, e. g. those where R R R and R are alkyl or aralkyl radicals and. where R is an alkyl'radical. I

comprise methyl, ethyl, propyl, butyl, amyl, octyl and;

Examples of aralkyl comprise benzyl, phen'-.

Examples of alkyl the like. "ethyl, and thelike. The quaternaryammonium alkoxides particularly preferred are those wherein R R and R are straightchain alkyl radicals containing 1-4 car- 7 bon atoms, where R; is benzyl and where R is a branched or straight chain alkyl radical containing 2 to 6 carbon atoms. 1

As illustrative of the preparation of such keto-acid is the following Example 11 T o a suitable reaction vessel is added and intimately mixed approximately 19 parts by weight of 85% potassium hydroxide, approximately 100 parts by weight of water, and approximately 10 parts by weight of the levorotatory isomer of trans-l-formyl-l-(3-keto-6-carbomethoxy hexyl) Z-keto-l-methyl-l,2,5,8,9,IO-hexahydronaphthalene. This mix so obtained is heated to about 70 C. and held at this temperature for about two hours. The aqueous solution is cooled and admixed with an equal volume of diethyl ether. The ether layer is discarded. The aqueous layer is then acidified with hydrochloric acid and extracted with several portions of diethyl ether. The extracts are combined, washed with water, dried and subjected to vacuum distillation. The solid residue is triturated with 75 parts by weight of a mixture of diethyl ether and petroleum ether, filtered and dried. The crystalline product so obtained is the levorotatory isomer of anti-trans-l-(fl-carboxyethyl)-2-ketol4-methylA -octahydrophenanthrene, M. P. 101- 102 C., [a] =374 (C=2,CHCl

In a similar fashion dl-anti-trans-l-(,B-carboxyethyl)- 2-keto-14-methyl-A -octahydrophenanthrene is obtained from dl-trans-1-forrnyl-(3-keto-6-carbomethoxyhexyl) 2-keto-10-methyl-1,2,5,8,9,IO-hexahydronaphthalone.

in the third step of the process described herein the carboxy group of compound III is esterified in an acid medium with an anhydrous short chain alcohol such as methanol, ethanol, isopropanol, butanol, and the like to provide an ester (compound IV) of the structure Example 111 To a suitable reaction vessel is added and intimately mixed 100 parts by weight of the levo-rotatory isomer of anti-trans l-(fl-carboxyethyl)-2-keto-14-methyl-A octahydrophenanthrene, 350 parts by weight of methyl alcohol and 17.5 parts by weight of anhydrous hydrochloric acid. The mixture is heated at 65 C. for about 4 hours.- The solvent is removed under vacuum and the residue is taken up with diethyl ether, washed with aqueous sodium carbonate, then with water and dried. Upon removal of the solvent by vacuum distillation a light yellow oily product identified as the methyl ester of the levo-rotatory isomer of anti-trans-l-(fl-carboxyethyl)-2- keto 1 methyl A -octahydrophenanthrene is obtained.

Similarly the methyl ester of dl-anti-trans-l-(fl-carboxy-' ethyl) 2-keto-14-methyl-A fl octahydrophenanthrene As illustrative is obtained from dl-anti-trans-l-(,B-carboxyethyl)-2-keto- 14-methyl-A -octahydrophenanthrene and anhydrous methyl alcohol in an acid medium. Other acidic esterification catalysts than hydrochloric acid may be employed, for example sulfuric acid.

In the fourth step of the process outlined herein the keto-acid ester (compound IV) is converted to the 6,7- cis-glycol (compound V) by treatment of the former with the silver salt of a low molecular weight fatty acid such as acetic acid and bromine or preferably iodine in the presence of a low molecular weight fatty acid such as acetic acid and then hydrolyzing the half esters so produced. As illustrative of this step is the following.

Example IV 21.6 parts by weight of the methyl ester of the levorotatory isomer of anti-trans-l-(B-carboxyethyl)-2-ketol4- methyI-A octahydrophenanthrene is dissolved in 794 parts by weight of glacial acetic acid and thereto is added and intimately mixed 26.0 parts by weight of silver acetate and 18.5 parts byweight of iodine. To the mix is added 2.5 parts by weight of water and the mix agitated for about 1 hour at 25 C. The mixture is heated to -100 C. and maintained at that temperature for about 3 hours. The reaction mixture is cooled and filtered and the filtrate subjected to vacuum distiller-- tion to remove the bulk of the acetic acid solvent. The residue is then taken up with 400 parts by weight of methyl alcohol and neutralized with potassium hydroxide. To the solution so neutralized is added 209 parts by weight of a 4.5% by weight methanol solution of potassium hydroxide and the mixture allowed to stand for about 16 hours at 25 C. under .an atmosphere of nitrogen. The solution is then neutralized with 37% hydrochloric acid and subjected to vacuum distillation. The residue is then taken up with chloroform and washed with three portions of a saturated sodium chloride solution. The chloroform solution is dried over magnesium sulfate and filtered. The filtrate is subjected to vacuum distillation. The oily residue contains a small amount of the levorotatory isomer of anti-trans-l-(B-carboxyethyl)-2-keto- 6,7 dihydroxy-l4-methyl-A -decahydrophenanthrene and principally its methyl ester. The oily residue so obtained is then taken up with anhydrous methanol and heated in the presence of a small amount of anhydrous hydrochloric acid. The reaction mass is subjected to vacuum distillation and the oily residue so obtained taken up withchloroform, washed with several portions of a saturated sodium chloride solution and then with water. The chloroform solution is dried over magnesium sulfate and the so dried solution subjected to vacuum distillation. The colorless oily residue is methyl ester of the levo-rotatary isomer of anti-trans-l-(fi-carboxyethyl)-2-keto-6,7-dihydroxy-l4-methyl-A -decahydrophenanthrene.

In a similar fashion the methyl ester of dl-anti-trans-l- (,8 carboxyethyl) 2 keto 6,7 dihydroxy l4- rnethyl-A -decahydrophenanthrene is obtained from the methyl ester of dl-anti-trans-l-(u-carboxyethyl)-2- keto-l4-rnethyl-A -octahydrophenanthrene.

In the fifth step of the process outlined herein the 6,7- glycol (compound V) is reacted with a cyclic acetal forming agent in the presence of a dehydrating catalyst. The preferred cyclic acetals (compound VI) so produced are those obtained from the symmetrical ketones such as acetone, diethyl ketone, cyclohexanone, p-methylcyclohexanone, etc. As illustrative of this stepis the following.

. 6,7-dihydroxy-14-methyl-A -decahydrophenanthrene,

M. P. 122424 (3., tot]D =242.5* c=2, CHCl In asimilar fashion the acetonide of. the methyl ester of dl-anti-translfi-carboxyethyl) -2-k eto-6,7-dihydroxy- 14 methyl A decahydrophenanthrene is obtained 7 from the methyl ester of dl-anti-trans-l-(fi-carboxyethyl)- 2-keto-6,7-dihydroxy-l4-methyl-A -decahydrophenanthrene.

In the sixth step of the process outlined herein the' 9,10-double bond of the acetonide (compound V1) is selectively'reduced in the presence of palladium. The reduction is preferably carried out in a liquid medium,

. such as an inert organic solvent incapable of hydrogenation under the conditions of the reaction. such are benzene, toluene, xylene, ethyl benzene, cyclo- Examples of hexane, the liquid alkanes, the lower aliphatic'alcohols,

etc. Asillustrative of'this step is the following.

Example ,VI

7' Approximately 20 parts by weight of the levo-rotatory V isomer of the acetonide of the methyl ester of anti-trans-l- (B carboxyethyl) 2 keto 6,7 dihydroxy 14- methyl-A -decahydrophenanthrene is admixed in a suitable reaction vessel with approximately 160 parts by weight of'isopropanol, approximately 0.3 part by Weight of aqueous sodium hydroxide and 4 parts by weight of a 2% palladium-strontium carbonate catalyst (which had been previously reduced). While agitating, gaseous hydrogen is passed into the mixture at about 25 C. at a pressure slightly above atmospheric. jAfter absorption of substantially one molar equivalent (approximately 0.0535 mol) of hydrogen the catalyst is filtered oil and the filtrate neutralized with acetic acid' and subjected to vacuumdistillation to're'move the solvent. Theresidue istaken up with chloroform, :washed with aqueous sodium bicrabonate followed by awater Wash,

dried over magnesium sulfate; and 'then' evaporated to dryness. The white crystalline product so obtained is the 'lev'o-rotatoryisomerof the acetonide of the methyl ester of anti-trans-l-(fi-carboxyethyl)-2-keto 6,7-dihydroxy-14-methyl-A F -'dodecahydrophenanthrene, M. P.

: In a similar fashion the acetonide of the methyl ester of dl-anti-trans-l-(fi-carboxyethyl)-2-keto-6,7-dihydroxy- 14-methyl-A -dodecahydrophenanthrene is obtained by selectively reducing the acetonide of the methyl ester of dl-anti-trans-l-(B-carboxyethyl)-2-keto-6,7-dihydroxy- 14-methyl-A9 -decahydrophenanthrene employing palladium as the hydrogenation catalyst.

In the seventh step of the process outlined herein the acetonide (compound VII) is hydrolyzed with an acid to f the corresponding cis-glycol (compound VIII), namely 7 1- (fi-carboxyethyl) -2-keto-6,7-dihydroxy- 1 4-methy1-A dodecahydrophenanthrene where. R is a short chain alkyl group, which glycol is preferably not isolated but oxidized .(theeighth step of the process outlined herein) to'provide the dialdehyde, namely an alkyl ester of l-(B-carboxyethyl):2eket0-5,6- di (formylmethyl) 6-methyl A octahydronaphthalene (compound IX) H CH2C=O 0% 0/ w which dialdehyde 'is dissolvedin an aromatic hydrocarbon solvent and cyclized (ninth step of the process outlined herein) in the presence of a carboxylic acid salt of an organic nitrogen base such as piperidine acetate to pro vide the corresponding all yl ester of 3-forrnyl-3a-methyl 6- (,G-c arboxyethyl '-7-k etoA octahydropentanthrene l W y As illustrativefof the preparation of the alkyl ester of.

3-formyl-3a-methyl 6-(p-carboxyethyl) 7-keto-A -octahydropentanthrene (compound X) from the cyclic acetal the alkyl'ester of l-(fl-carboxyethyl)-2-keto-6,7-dihydroxy-l4-methyl-Al dodecahydrophenanthrene is the following i Example VII 9 parts by weight of the levdrotatory isomer of the acetonide of the ineth'yl ester of anti-trans-l-(B-carboxy ethyl)-2-keto-6,7-dihydroxy 14 methyl-A i-dodecahy drophenanthrene is dissolved in approximately. 60 parts by Weight of acetic acid, Thereupon 60 parts by: weight of water-is added intimately mixed and the solution heated oii a steam bath for one hour. The solutionis cooled to -05 -cpand approximately'zlq parts by weight or water is. added- To the solution of' thecis-glycol so preparedis added at about-015 11.25 parts by weight of lead tetraacetate andfZlO parts by weight of acetic acid. The slurry so obtained is agitated for about 10 minutes, and thereafter is added with agitation approximately parts by weight of ,water. Themixture is then extracted with two 375 parts bylweight portions of chlorform. The extracts are combinedand Washed successively with dilute aqueous sodium bicarbonate, 200 r parts by weight of 1N sulfuric acid, dilute aqueous sodium bicarbonate, and finally. 'with' water. The so washed solution is dried over magnesium isulfate,'-filtered and:

the filtrate subjected to vacuum distillation. The oily residue is the dialdehyde, which is taken up with approximately 1350 parts by' weight of' anhydrous benzene 'and' heated 10 80 C." Thereto is added with agitationapproximately 3parts by weight of acetic acid and approximately 2 partsby Weight of piperidine.

while passing nitrogen over the 'mixture and'slowly-distilling the water-benzene,azeotrope. The reaction mixture is cooled to roomtemperature and washed successively .with .dilute hydrochloric 'acid, dilute sodium bicar bonate and finally with water. The solution is dried over anhydrous magnesium. sulfate and theso dried'solu tidn subjected toyacuum distillation. Upon, recrystallization of the residue so obtained from diethyl ether, the dextro-rotatory methyl ester of anti-trans-3-formyl- 3a-me'thyl-6-(fl-carboxyethyl) 7 -.keto-A .'5 -octahydro- :pentanthrene M.B;..70 72 C., is obtained. .1 5

I The mix so obtained is heated at 80 C. for about one hour Similarly the methyl ester of dl-antitrans-3-formyl-3a methyl-G-(fi-carboxyethyl) 7 keto-n -octahydropentanthrene is obtained by the acid hydrolysis of the acetonide of the methyl ester of dl-anti-trans-l-(fi-carboxyethyl)-2-keto-6,7-dihydroxy-14-'nethyl-A -dodecahydrophenanthrene, cleavage of the glycol so obtained followed by ring closure of the dialdehyde so produced.

In the tenth step of the process outlined herein the 2,3-double bond of the alkyl ester of 3-formyl-3a-methyl- 6-(B-carboxyethyl) 7-ketoA -octahydropentanthrene (compound X) is selectively reduced in the presence of palladium to provide the alkyl ester of 3-formyl-3a-methyl-6-(fi-carboxyethyl) 7 hem-A -decahydropentanthrene (compound XI) The reduction is preferably carried out in a liquid medium, such as for example in the presence of an inert organic solvent incapable of hydrogenation under the conditions of the reaction. As illustrative of this step is the following Example VIII Approximately 35.8 parts by weight of the dextro-rotatory methyl ester of anti-trans-fl-formyl-Ba-rnethyl-6-(B- carboxyethyl)-7diets-A -octahydropentanthrene is admixed in a suitaoie reaction vessel with approximately 800 parts by weight of isopropanol and approximately 15 parts by weight of a 2% palladium-strontium carbonate (which had been previously reduced). While agitating, gaseous hydrogen is passed into the mixture at about 25 C. at a pressure slightly above atmospheric. After absorption of substantially one molar equivalent (approximately 0.114 mole) of hydrogen, the catalyst is filtered off and the filtrate subjected to vacuum distillation. The oily residue is the deXtro-rotatory methyl ester of anti-trans 3 forn1yl-3a-methyl-fi-(fl-carboxyethyl)-7- keto-A -decahydropentanthrene.

In a similar fashion the methyl ester of dl-anti-trans- 3 formyl 3a methyl 6 (,8 carboxyethyl) 7 keto- A -decahydropentanthrene is obtained from the methyl ester of dl anti trans 3 formyl 3a methyl 6- (13 carboxyethyl) 7 keto ti octahydropentanthrene employing palladium as the reduction catalyst.

In the eleventh step of the process outlined herein the mono-ethylene ketal, namely an alkyl ester of 3-[2-(1,3- dioxacyclopentanyl)] 3a methyl 6 ([3 carboxyethyl) 7 keto A5545) decahydropentanthrene (compound XIII) is prepared by condensing an alkyl ester of 3 formyl 3a methyl 6 (,8 carboxyethyl) 7 keto- N decahydropentanthrene with an equimolecular amount of ethylene glycol in the presence of an acid condensation catalyst. As illustrative of this process step is the following Example IX Approximately 35 parts by weight of the dextro-rotatory isomer of the methyl ester of anti-trans-3-formyl- 3a methyl 6 (B carboxyethyl) 7 keto A decahydropentanthrene of Example VIII is dissolved in mixture of about 2500 parts by weight of dioxan and 4500 parts by weight of benzene. Thereto is added and intimately mixed about 7.8 parts by weight of ethylene glycol and approximately 1 part by weight of p-toluene sulfonic acid. The reaction mass is brought to reflux and the benzene-water azeotrope slowly distilled off. Thereafter the mass is subjected to vacuum distillation to remove the solvent. The residue is taken up with chloroform, and the chloroform solution washed with aqueous potassium carbonate followed by a water wash. The chloroform solution is dried and subjected to vacuum distillation. The residue on recrystallization from diethyl ether gives white crystals of the optically active isomer of the mono-ethylene ketal of the methyl ester antitrans 3 formyl 3a methyl 6 (B carboxyethyl) 7 keto A536) decahydropentanthrene, M. P. 99- 101 C.

. In a similar fashion the methyl ester of dl-anti-trans- 3 [2 (1,3 dioxacyclopentanyD] 3a methyl 6- (B carboxyethyl) 7 lteto A decahydropentanthrene is obtained upon condensing ethylene glycol with the methyl ester of dl-anti-trans-3-formyl-3a-methyl-6- (/3 carboxyethyl) 7 lzeto N decahydropentanthrene in the presence of an acid condensation catalyst.

In the twelfth step of the process outlined herein an angular methyl group is introduced to the 6-position of the pentauthrene nucleus by reacting methyl iodide (or like methylating agents such as dimethyl sulfate, methyl tosylate, -etc., with the allryl ester of 3-[2-(1,3-dioxacyclopentauyl)] 3a methyl 6 8 carboxyethyl) 7- keto A5946) decahydropentanthrene (compound XII). In the introduction of the angular methyl group a new asymmetric center'is introduced and thus a mixture of stereoisomers results. This mixture is preferably not isolated and separated into its isomeric parts, but converted directly by hydrolysis (step thirteen of the process outlined herein) to the corresponding carboxy ethyl deriva tive (compound XIV). The carboxy ethyl derivative so obtained is a mixture of isomeric anti-trans-3-[2-(1,3-dioxacyclopentanyD] 3a 6 dimethyl 6 (B carboxyethyl) 7 keto A decahydropentanthrene, which isomers for purposes of this invention may be represented structurally and defined as follows Although both of the isomeric uand B-keto acids may be converted to a tetracyclic ketone of the general structure of compounds XV, XVI and XVII of the diagram set forth hereinbefore the B-keto acid as identified herein produces a tetracyclic ketone of the perhydrocyclopentanophenanthrene series whose angular methyl groups are on the same side of the cyclopentanophenanthrene reference plane while the a-keto acid provides a tetracyclic ketone whose an ular methyl groups are on opposite sides.

As illustrative of the introduction of the angular methyl group in the 6-position of the pentanthrene nucleus of an alkyl ester of 3-[2-(1,3-dioxacyclopentanyl)I-Ba-methyl 6 (B carboxyethyl) 7 keto A decahydropentanthrene to provide an alkyl ester of 3-[2-(1,3-dioxacyclopentanyl)] 3a,6 dimethyl 6 (,3 carboxyethyl)- 7 keto A decahydropentanthrene (compound XIII) and conversion to the free acid following (compound XIV) is the Example 12.22 parts by weight of the mono-ethylene ketal of the optically active methyl ester of anti-trans 3-formyl-3a-- methyl -'6 (B -'carboxyethyl)' 7 "keto A 5 deca- 'hydropentanthrene of Example IX is 'dissolvedin a mix- 'ture of about 360 parts by weight of benzeneand. about the methyl. iodide addition the reaction mass is refluxed for about 5 minutes. The mix is cooled to room temperature. This solution which containsthe respective methyl esters of the tand j3-anti-trans-keto acids in'a weight ratio'of approximately 1 to 2 is admixed with 200 parts by weight of water in order to hydrolyze the esters. The organic layer is separated and extracted with dilute aqueous potassium hydroxide. The organic layer is separated and cooled to about 0-5 C., admixed with an equal volume of diethyl ether and the mix then acidified with dilute sulfuric acid. The aqueous layer is removed and extracted with two equal volumes of diethyl ether, The ether extracts are combined, washed with water and dried. :Upon removal of the ether by vacuum distillation approximately 11.96 parts by; weight of an oil consisting of the a and 8 isomers of the respective ke to-acids in weight ratio of approximately 1 to 2 is obtained.

If desired the oilyrnixture of aand fi-keto acids may be separated into its component parts by various Well known methods. As for example by dissolving the oil in a low molecular weight alkanol such as methanol,

admixing therewith a chemically equivalent weight of quinine, and refluxing the reaction mass. Upon cooling to room temperature or below the respective quinine salts may be effectively separated by fractional crystalliza-. tion. The respective quinine salts on treatment with an alkaline material more basic than quinine in an aqueous medium, followed by separating the free quinine by filtration, and subsequently acidifying with mineral"; acid yields the respective aand B-keto. acids in separated form. In general, however, the mixture is not separated into its component keto-acid isomeric parts but boiled (step fourteen of the. process outlined'herein) with acetic anhydride in the presence of a small amount of sodium acetate. By so doing'thejenol lactone (compound XV), e. g. 3-keto-17-[2-(1,3-dioxyacyclopentanyl)]-cyclophentano-10,l3-dimethyl A1901) L 4 oxa decahydrophenanthrene, is obtained as a mixture of isomers which may be represented structurally and defined as follows ooHi ooni acids obtained in Example X is dissolved in 162 parts by weight of acetic 'anhydride containing 01 part by weight of sodium acetate and refluxed for four hours under an atmosphere of nitrogen. The reaction mass is then cooled. The acetic anhydricle is removed by vacuum distillation and-the residue taken up with diethyl ether.

The solution is washed with aqueous sodium bicarbonate,

followed a water wash and dried. Upon removal of the ether by vacuum distillation an oil is obtained which on standing crystallized. The weight yield is 9.95 parts by weight of a mixture of 0tand 8-enol lactones in about a' 1 to 2 weight ratio. a t i a In the fifteenth step of the process outlined herein the enol lactone (compound XV) is converted to the corresponding tetracy'cli'c'ketone (compound XVI), i. e. the mono-ethylene ketal of '3-keto-17-formyl-cyclopentano 10,l3-dimethyl-A 9 -decahydrophenanthrene, by reacting the former with a methyl magnesium halide'indiethyl. ether, decomposing the addition product with mineral acid, and then treating'the ether solubles with an alcohol solution of an alkali metal hydroxide. This step affords the means for conveniently separating the unwanted stereoisomer from the desired stereoisomer and as illustrative thereof is the following Example XII bromide while maintaining the temperature below '-50 C. Upon completion of the methyl magnesium bromide addition the mix is stirred at to C. forabout 90 minutes. Thereafter approximately 50 parts by weight of acetone, approximately parts by weight of Water and approximately 20 parts by weight of acetic acid is added and intimately mixed and the mix permitted to rise to about 0 C. The layers are separated and the v by weight of an oily'residue which partially crystallized ether extract washed with aqueous sodium carbonate, water washed, driedand subjected to vacuum distillation. The oily residue is taken up with 400 parts by weight of methyl alcohol and thereto is added 72 parts by weight of 16.7% aqueous solution of potassium hydroxide and the mixture so' obtained refluxed for about 2 hours under a nitrogen atmosphere. Thereupon substantiallyv all of the methanol is removed by vacuum distillation- An equal volume of water is added to the residue, and the resultant mix extracted twice with equal volumes of chloroform. The extracts are combined, dried and subjected to vacuum distillation. Approximately 6.51 parts on standing is obtained. The residueis dissolved in methanol and set asideto permit crystallization. Upon filtration white crystals ofthe optically active .monoethylene. ketal of .3A -2l-norprogesterone, M. P. l72,I75TC.. [a] '-|-70.6 (C=2,CHCl is obtained. 'In afsimilar manner the mono-ethylene ketal of white crystalline all-A -Zl-norprogesterone is obtained by proceeding through the processes set forth in Examples X and :XI beginning with the alkyl ester of dl-anti-trans-3- [2-(1,3 dioxacyclopentanyl)]3a-methyl-6-(;3 carboxy-v ethyl) -7-keto-A (6) -decahydrop entanthreneJ "In the sixteenth step of the process outlined herein the mono-ethylene ketal (compound XVI) is converted to the corresponding l7-formyl-cyclopentano-1 0,13 'dimethyl- A -decahydrophenanthrenea3-one (compound XVII) by heating the former in the presence of an acid. As illustrative of such is the following a i a e r e 7 Example. XIII 5 parts by weight of the mono-ethylene ketal obtained by the process of Example XI is heated with 5000 parts byweight of-50% aqueous acetic acid at 100 C. for approximately minutes. The reaction mass is subjected to vacuum distillation and the residue taken up with chloroform. 'The chloroform solution is washed with aqueous sodium bicarbonate and finally with water and dried. .zThe1oil.residue;oifcrystallization gives white;

13 crystalline dextro-rotatory isomer of A -21-norprogesterone, M. P. 127131 C.

Similarly til-A -21-norprogesterone is obtained from the mono-ethylene ketal of dl-A -2l-norprogesterone.

The compound of Example XII so obtained is identical with that obtained by reacting one molar equavilent of hydrogen with the deXtro-rotatory isomer of A -2lnorprogesterone (M. P. 160.516l.5 C.) in the presence of palladium and is described and claimed in co-pending application Ser. No. 426,311, filed April 28, 1954, of Harold Raiielson. This optically active isomer upon reacting with methyl magnesium bromide, hydrolyzing the complex so obtained,'followed by oxidation with chromic acid in the presence of pyridine provides for the dextrorotatory isomer of M -progesterone.

While this invention has been described with respect to certain embodiments it is to be understood that it is not so limited and that variations and modifications thereof obvious to those skilled in the art may be made Without departing from the spirit or scope of the invention.

Compounds of the structural formulae of that of compounds III and IV of the foregoing diagram are claimed in co-pending application Serial No. 436,718, filed of even date, of Quentin E. Thompson and Harold Ratfelson.

Compounds of the structural formulae of that of compounds V and VI of the foregoing diagram are claimed in co-pending application Serial No. 436,723, filed of even date, of William S. Knowles.

Compounds of the structural formula of that of compound VII of the foregoing diagram are claimed in copending application Serial No. 436,719, filed of even date, of Harold Rafielson.

Compounds of the structural formulae of that of compounds VIII, IX, X, XI, XII, XIII, XIV, XV and XVI of the foregoing diagram are claimed in co-pending application Serial No. 436,722, filed of even date of Lloyd B. Barkley.

What is claimed is:

1. As a new compound the 1evo-rotatory isomer of trans 1 formyl 1 (3 keto 6 carboalkoxy hexyl) '2 keto 10 methyl 1,2,5,8,9,10 hexahydronaphthalene of the structural formula where R is a short chain alkyl radical.

2. The levo-rotatory isomer of trans-1-formyl-1-(3- keto 6 carbomethoxy hexyl) 2 keto 10 methyl 1,2,5,8,9,IO-hexahydronaphthalene.

References Cited in the file of this patent UNITED STATES PATENTS 2,617,828 Sarett et a1 Nov. 11, 1952 2,672,482 Woodward Mar. 16, 1954 2,702,805 Woodward Feb. 22, 1955 OTHER REFERENCES Woodward et al.: J. Am. Chem. Soc. 74, 4227, 4240 (1952). 

1. AS A NEW COMPOUND THE LEVO-ROTATORY ISOMER OF TRANS-1- FORMYL-1-(3- KETO-6-CARBOALKYLOXY-HEXYL) 2 - KETO- 10 - METHYL - 1,2,5,8,9,10 - HEXAHYDRONAPHTHALENE OF THE STRUCTURAL FORMULA 